Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:29])[CH3:28])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH:27]([CH3:28])[CH3:29])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CN(CC)C3CC3)c(C(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Using General Procedure I; a solution of ethyl 4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-isopropyl-phenylethynyl}-benzoate (Compound 133, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (600.0 mg, 15.0 mmols, 3.0 mL of a 5N aqueous solution) and stirred overnight at room temperature and then at 55° C. for 9 hours. Work-up followed by crystallization of the solid residue from hot CH3CN afforded 45.0 mg (.72%) of the title compound as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5]Br.[C-:14]#[N:15].[Na+].O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5][C:14]#[N:15]
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1CC#N
Reaction time: 0.17 h

Procedure:
To a solution of 2-methoxy-5-nitrobenzyl bromide (984 mg) in dimethylsulfoxide (5 mL) was added sodium cyanide (216 mg) and the mixture was stirred at 80 degrees for 10 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate, and concentrated to give the title compound having the following physical data. The obtained title compound was used to next reaction without further purification.
Reaction SMILES: [CH2:1]([P:6](=[O:11])([O-:10])[O:7][CH2:8][CH3:9])P(=O)([O-])[O-].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH:36]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH:37]=O)=[C:29]([Cl:47])[CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].[CH2:50]1COC[CH2:51]1>>[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([S:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH:36]([NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH:37]=[CH:1][P:6](=[O:11])([O:10][CH2:50][CH3:51])[O:7][CH2:8][CH3:9])=[C:29]([Cl:47])[CH:28]=2)[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOP(=O)([O-])CP(=O)([O-])[O-]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC(C=O)CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CCOP(=O)(C=CC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C)OCC
Reaction time: 0.5 h

Procedure:
Ethyl methylenebisphosphonate (940 mg) in THF (5 mL) was chilled to −78° C. under an argon gas atmosphere. To this solution, a 1.6 mol/L n-BuL-hexane solution (2 mL) was added dropwise and the mixture was stirred for 30 min, followed by dropwise addition of a THF solution (15 mL) of the compound of Example 193 (1.58 g). After 3 hours, a saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of sodium chloride and was dried over anhydrous sodium sulfate. The solvent was removed by distillation to give the desired product as a colorless oil (1.71 g).
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][C:15](O)=[S:16])=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]1[CH2:28][CH2:27][N:26]2[C:21](=NC[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:25]([N:26]([CH:21]1[CH2:20][CH2:19][CH2:18][CH2:28][CH2:27]1)[C:15](=[S:16])[CH2:14][CH2:13][CH2:12][C:11]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=[N:9][N:10]=1)[CH3:24]
Reactant: OC(=S)CCCc1nnnn1C1CCCCC1
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)CCCc1nnnn1C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(1-Cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine (54 mmole), and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-4-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 47%), colorless liquid, nD18 =1.5290.
Reaction SMILES: C[Mg]Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[C:15](OCC)(=O)C.Cl>O1CCCC1.O>[OH:14][C:12]([CH3:15])([CH3:13])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of methyl magnesium bromide (3 M, 14 mL, 39.94 mmol) cooled to 0° C. was added tetrahydrofuran (10 mL) and as solution of 1-(4-hydroxy-phenyl)-propan-2-one (1 g, 6.66 mmol) in tetrahydrofuran (30 mL). The resulting mixture was then warmed to room temperature and then stirred for 2 h. At this time, the reaction was partioned between ethyl acetate and water. The water layer was made acidic with 1N aqueous hydrochloric acid (pH=1). The organic phase was separated and concentrated in vacuo. The residue was dissolved in a small volume of tetrahydrofuran and the mixture was treated with an excess of hexanes. This resulted in the precipitation of the product 4-(2-hydroxy-2-methyl-propyl)-phenol (0.85 g, 77%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:46]>C(Cl)Cl.C(OCC)C>[ClH:46].[ClH:46].[NH2:7][CH:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)CC(N)CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 0.42 h
Yield: 61 %

Procedure:
To a solution of (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester (0.4 g, 0.76 mmol, Example 7, Step B) in CH2Cl2 (7.5 mL) was added trifluoroacetic acid (2.5 mL) at ambient temperature under nitrogen atmosphere. The resulting reaction mixture was stirred for 25 minutes, then concentrated in vacuo. The viscous oil obtained was dissolved in 40 mL of CH2Cl2 and successively washed with saturated aqueous NaHCO3 solution (2×40 mL), brine (2×40 mL), and was dried over Na2SO4. The CH2Cl2 solution of free amine was concentrated in vacuo to afford the crude product as a viscous oil which was then dissolved in 10 mL of ethyl ether. To this solution was added saturated HCl solution in ethyl ether until no more white precipitate formed. Filtration and drying overnight under vacuum afforded 0.23 g (61%) of titled compound as a yellow solid; mp 228-230° C.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=O)[O:17]CC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[NH:21]([C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22].O>CN1C(=O)CCC1>[OH:17][C:16]1[N:22]2[N:21]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:2]=[C:1]2[CH:3]=[C:4]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)[N:15]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)NN
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1nc2cc(-c3ccc(C(F)(F)F)cc3)nc(O)n2n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.4 g (8.4 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.24 g (8.4 mmol) of ethyl hydrazino(oxo)acetate are dissolved in NMP (16 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and poured into water (100 ml), and the precipitate is filtered off, washed with water and diethyl ether and dried. 1.90 g (64% of theory) of the crude product are obtained.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.[OH-].[Na+]>C(OCC)(=O)C>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To tetrahydrofuran (120 mL) were added 4-bromobenzoyl chloride (25 g), (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (30 g) and 1N aqueous sodium hydroxide solution (250 mL), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was recrystallized to give the title compound (46 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)=[CH:5][CH:4]=1)#N.[OH-:28].[K+].Cl.[CH2:31](O)[CH2:32][OH:33]>O>[CH2:32]([O:33][C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:27])([CH3:26])[CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)=[CH:5][CH:4]=1)=[O:28])[CH3:31].[C:4]([C:5]1[CH:1]=[CH:3][CH:8]=[CH:7][C:6]=1[C:9]([CH3:26])([CH3:27])[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=1)([OH:33])=[O:28]
Reactant: [OH-]
Reactant: OCCO
Reactant: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccc(C#N)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(COCc1cccc(Oc2ccccc2)c1)c1ccccc1C(=O)O
Product: CCOC(=O)c1ccc(C(C)(C)COCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
3-Phenoxybenzyl 2-(4-ethoxycarbonylphenyl)-2-methylpropyl ether was synthesized according to the following procedures. (1) A mixture of 3.5 g of 3-phenoxybenzyl 2-(4-cyanophenyl)-2-methylpropyl ether, 7.0 g of potassium hydroxide, 7.0 g of water and 20 ml of ethylene glycol was stirred at 130° C. for 4.0 hours. The mixture was cooled to room temperature, and water was added and the mixture was made acidic by addition of hydrochloric acid. Then, the mixture was extracted with ether, and the ether extract was washed with water, dried over Na2SO4, and evaporated to give 3.1 g of 3-phenoxybenzyl 2-(carboxyphenyl)-2-methylpropyl ether (mp. 98.5°-102.5° C.).
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and CuI (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].[C:13]([O:17][CH3:18])(=[O:16])[C:14]#[CH:15].O=C1O[C@H]([C@H](CO)O)C(O)=C1O>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]1[CH:15]=[C:14]([C:13]([O:17][CH3:18])=[O:16])[N:7]=[N:6]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C#CC(=O)OC
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CCO
Product: COC(=O)c1cn(Cc2c(F)cccc2F)nn1
Reaction time: 8 h
Yield: 94 %

Procedure:
2,6-Difluorobenzyl azide (3.0 g, 17.7 mmoles) is suspended in ethanol (30 ml), then methyl propiolate (IV) (1.6 g, 19.6 mmoles), ascorbic acid (317 mg, 1.8 mmoles) and CuSO4 pentahydrate (50 mg, 0.18 mmole) are added. The reaction mixture is kept at 25° C. under stirring overnight. The mixture is concentrated, taken up with ethyl acetate and washed with an ammonia diluted solution. The organic phase is dried, filtered, concentrated under reduced pressure. A crystalline white solid is obtained in 94% yield.
Reaction SMILES: [S:1]1C=C[CH:3]=[C:2]1CC(O)=O.[CH2:10]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH:24](Br)[C:25]([OH:27])=[O:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:29]>C(=O)([O-])[O-].[K+].[K+]>[C:2]([S:1][CH:24]([CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19])[C:25]([OH:27])=[O:26])(=[O:29])[CH3:3]
Reactant: O=C(O)Cc1cccs1
Reactant: O=C(NCCCC(Br)C(=O)O)OCc1ccccc1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)SC(CCCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiolacetic acid (1 g.) is added to a solution of 5-benzyloxycarbonylamino-2-bromopentanoic acid [Chem. Pharm. Bull., 24, 326 (1976)] (3.3 g.) in a mixture of water (30 ml.) and potassium carbonate (1.38 g.). The mixture is stirred at room temperature overnight, acidified and extracted with ethyl acetate to yield 2-acetylthio-5-benzyloxycarbonylaminopentanoic acid.
Reaction SMILES: ClCCl.[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:27]4[N:31](CCC#N)[N:30]=[N:29][N:28]=4)=[C:24]([CH3:26])[N:25]=3)[CH2:17][C@H:16]2[O:36][CH3:37])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl>C(OCC)(=O)C.O>[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:27]4[NH:28][N:29]=[N:30][N:31]=4)=[C:24]([CH3:26])[N:25]=3)[CH2:17][C@H:16]2[O:36][CH3:37])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnnn4CCC#N)s3)C[C@H]2OC)nc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(-c4nnn[nH]4)s3)C[C@H]2OC)nc1Cl
Yield: 51.6 %

Procedure:
Dichloromethane (1.5 mL) was added to cis(±)-4-chloro-N-(1-{5-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]-4-methyl-1,3-thiazol-2-yl}-3-methoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxylic acid amide obtained in Example (262a) (16 mg, 0.03 mmol). While the mixture was stirred, diazabicycloundecene (15 mg, 0.10 mmol) was added, followed by stirring at room temperature overnight. The reaction solution was diluted with ethyl acetate and water. The organic layer was neutralized with 1 N hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was solidified with diethyl ether and hexane to obtain 7 mg of the title compound as a white solid (47%).
Reaction SMILES: C([N:10]=[C:11]=[O:12])CCCCCN=C=O.[CH:13]1C=C(CN=C=O)C=C(CN=C=O)[CH:14]=1.[C:27]([O-:40])(=[O:39])[CH2:28][CH2:29]CCCCCCCCC.C([Sn+2]CCCC)CCC.C([O-])(=[O:62])CCCCCCCCCCC.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:27]([OH:40])(=[O:39])[CH:28]=[CH2:29].[NH2:10][C:11]([O:12][CH2:13][CH3:14])=[O:62]
Reactant: O=C=NCCCCCCN=C=O
Reactant: O=C=NCc1cccc(CN=C=O)c1
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C

Procedure:
50 parts of toluene, 25 parts of hexamethylene diisocyanate subjected to isocyanurate modification (“TAKENATE D-170N”), 162.8 parts of polycaprolactone-modified hydroxyethyl acrylate (“PLACCEL FA10”, trade name, produced by Daicel Chemical Industries, Ltd.), 0.02 parts of dibutyltin laurate, and 0.02 parts of hydroquinone monomethyl ether were mixed and the mixture was maintained at 70° C. for 5 hours. Thereafter, 137.8 parts of toluene was added to obtain a urethane acrylate having a solid content of 50% by weight. The number of repetitions of a caprolactone unit per one residue of the acrylate monomer in the obtained urethane acrylate is 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]([C:11]2([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[O:17])[CH2:14][CH:13](O)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:30]1(=[O:44])[N:34]([CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40](O)=[O:41])[C:33](=[O:43])[CH:32]=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][O:18][C:16]([C:11]2([C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)=[O:10])[CH2:14][CH:13]([C:40](=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35][N:34]3[C:30](=[O:44])[CH:31]=[CH:32][C:33]3=[O:43])[CH2:12]2)=[O:17])=[CH:21][CH:22]=1
Reactant: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(O)C2)cc1
Reactant: O=C(O)CCOCCN1C(=O)C=CC1=O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2(C(=O)OCc3ccc(OC)cc3)CC(C(=O)CCOCCN3C(=O)C=CC3=O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of PMB-CB-OH (1.97 g, 4.91 mmol), 6-maleinimido-4-oxacaproic acid (1.57 g, 7.37 mmol) and triethylamine (2.04 ml, 8.64 mmol) is admixed with 2-chloro-1-methylpyridinium iodide (1.88 g, 7.37 mmol) in 30 ml anhydrous dichloromethane and stirred for three hours at room temperature. It is diluted with 140 ml dichloromethane, washed each time twice with 80 ml in hydrochloric acid, 80 ml water and once each time with 80 ml sodium chloride solution (saturated) and dried over magnesium sulfate. Subsequently the solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel, chloroform/methanol 200:1). 2.89 g PMB-CB-1-Mal (99% of theory) is obtained as a colourless oil.
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]4=[O:28])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:5]1.CO>CN(C)C=O>[C:1]([CH2:5][C:6]1([OH:4])[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)#[N:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by reacting potassium cyanide (20.7 mmol) with (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (13.8 mmol) in 60 ml 5:1 methanol: dimethylformamide mixture under stirring. The reaction was stirred for 12 hours at 25° C. and quenched with saturated ferrous sulfate solution. The reaction mixture was filtered. The filtrate was extracted with ethyl acetate, organic layer was washed with brine and dried over sodium sulfate. Evaporation of organic solvent under vacuum and silica gel chromatographic purification afforded the titled product in 44% yield. M.P. 88-90° C. and MS (M+1)=373 (MH+, 100%) for M.F.=C19H24N4O4.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N(C2CCCC2)C(NC2SC=CN=2)=O)CCCC1.C(OC(=O)CNS(C1SC(N)=NC=1)(=O)=O)C>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH3:30])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1nccs1)N(C1CCCC1)C1CCCC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CCOC(=O)CNS(=O)(=O)c1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid (Example 76) via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine (General procedure 1) and (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: ClC1C=C2[C:8](=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)[C:6](C(OCC)=O)=C2S(Cl)(=O)=O.Cl[S:30]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35](S(C2C=CC=CC=2)(=O)=O)[C:34]=1[C:53]([O:55]CC)=O)(=[O:32])=[O:31].Cl.CN.C[NH:62]C>O1CCCC1.C(N(CC)CC)C>[CH3:6][N:7]([CH3:8])[S:30]([C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:42][CH3:43])[CH:40]=2)[NH:35][C:34]=1[C:53]([NH2:62])=[O:55])(=[O:32])=[O:31]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CNC
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(OC)ccc2n1S(=O)(=O)c1ccccc1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N(C)C)c2c1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with dimethylamine 2.0 M solution in tetrahydrofuran, and omitting triethylamine from the reaction mixture, the title compound was obtained. ESI+MS: 298.2 [M+H]+.